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Familial Investigations of Childhood Cancer Predisposition

ABSTRACT: NOTE: This is a research study and is not meant to be a substitute for clinical genetic testing. Families may never receive results from the study or may receive results many years from the time they enroll. If you are interested in clinical testing please consider seeing a local genetic counselor or other genetics professional. If you have already had clinical genetic testing and meet eligibility criteria for this study as shown in the Eligibility Section, you may enroll regardless of the results of your clinical genetic testing. While it is well recognized that hereditary factors contribute to the development of a subset of human cancers, the cause for many cancers remains unknown. The application of next generation sequencing (NGS) technologies has expanded knowledge in the field of hereditary cancer predisposition. Currently, more than 100 cancer predisposing genes have been identified, and it is now estimated that approximately 10% of all cancer patients have an underlying genetic predisposition. The purpose of this protocol is to identify novel cancer predisposing genes and/or genetic variants. For this study, the investigators will establish a Data Registry linked to a Repository of biological samples. Health information, blood samples and occasionally leftover tumor samples will be collected from individuals with familial cancer. The investigators will use NGS approaches to find changes in genes that may be important in the development of familial cancer. The information gained from this study may provide new and better ways to diagnose and care for people with hereditary cancer. PRIMARY OBJECTIVE: * Establish a registry of families with clustering of cancer in which clinical data are linked to a repository of cryopreserved blood cells, germline DNA, and tumor tissues from the proband and other family members. SECONDARY OBJECTIVE: * Identify novel cancer predisposing genes and/or genetic variants in families with clustering of cancer for which the underlying genetic basis is unknown.

DISEASE(S): Carcinoma,Pheochromocytoma,Anemia, Diamond-blackfan,Lynch Syndrome,Neurofibromatosis Type 1,Li-fraumeni Syndrome,Neoplasms,Multiple Endocrine Neoplasia,Hodgkin Lymphoma,Noonan Syndrome And Other Rasopathy,Rothmund-thomson Syndrome,Familial Wilms Tumor,Acute Leukemia,Emberger Syndrome,Pten Hamartoma Tumor Syndrome,Familial Adenomatous Polyposis,Familial Cancer,Mds,Dicer1 Syndrome,Neurofibromatosis Type Ii,Aml,Familial Neuroblastoma,Disease Susceptibility,Anemia,Adenomatous Polyposis,Adenomatous Polyposis Coli,Adrenocortical Carcinoma,Neurofibromatoses,Pancreatic Cancer,Constitutional Mismatch Repair Deficiency Syndrome,Colorectal Neoplasms, Hereditary Nonpolyposis,Rhabdoid Tumor Predisposition Syndrome,Dyskeratosis Congenita,Diamond-blackfan Anemia,Multiple Endocrine Neoplasia Type 2a,Carney Complex,Hereditary Breast And Ovarian Cancer Syndrome,Retinoblastoma,Juvenile Polyposis,Gist,Carcinoma, Basal Cell,Multiple Endocrine Neoplasia Type 2,Leukemia,Tuberous Sclerosis,Hamartoma Syndrome, Multiple,Rhabdomyosarcoma,Multiple Endocrine Neoplasia Type 1,Fanconi Anemia,Neurofibromatosis 2,Noonan Syndrome,Neurofibromatosis 1,Neuroblastoma,Hereditary Paraganglioma-pheochromocytoma Syndrome,Bap1 Tumor Predisposition Syndrome,Peutz-jeghers Syndrome,Paraganglioma,Gata2 Deficiency,Lymphoma,Nevoid Basal Cell Carcinoma Syndrome,Basal Cell Nevus Syndrome,Familial Acute Myeloid Leukemia,Hamartoma,Pheochromocytoma/paraganglioma,Rhabdoid Tumor,Hereditary Breast And Ovarian Cancer,Non Hodgkin Lymphoma,Overgrowth Syndromes,Endocrine Gland Neoplasms,Wilms Tumor,Melanoma Syndrome,Choroid Plexus Carcinoma,Von Hippel-lindau Disease,Neurofibroma

PROVIDER: 2236478 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer.

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Familial Investigations of Childhood Cancer Predisposition

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